Ran Pathway
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Ran Pathway

Ran is a member of the Ras family of small GTPases. The Ran subgroup is represented by its lone member, Ran, that is distinguished from RasGTPases by its lipid modification and atypical subcellular localization. Unlike most other Ras-related proteins, Ran is not modified to bind to cell membranes. Instead, Ran protein is localized throughout the cell, where it is concentrated primarily in the nucleus (Ref.1). Ran is regulated by a cytosolic RanGAP1 (Ran GTPase-Activating Protein-1) and by a RanGEF (Chromatin-Bound Guanine Nucleotide Exchange Factor). The distribution of RanGTP provides important spatial information that directs cellular activities during different parts of the cell cycle. During interphase, the localization of RanGEF and RanGAP1 predicts that nuclear Ran is GTP-bound and cytosolic Ran is GDP-bound. This compartmentalization determines the direction of nuclear transport by promoting the loading and unloading of transport receptors in a manner that is appropriate to the nucleus or cytosol (Ref.2).

Ran plays a critical role in nucleocytoplasmic transport of macromolecules through the NPC (Nuclear Pore Complex) and has been implicated in regulating cell cycle progression and microtubule assembly dynamics. Ran plays a central role in nuclear import and export pathways by promoting assembly and disassembly reactions of transport receptors and cargo (Ref.3). Proteins destined for the nucleus contain a NLS (Nuclear Localization Signal), whereas proteins destined for the cytoplasm contain a NES (Nuclear Export Signal). These transport signals are recognized by members of the importin/karyopherin superfamily of transport receptors, which escort NLS or NES cargo proteins through the NPC. Import receptors bind NLS cargo in the cytoplasm, and the import complex translocates to the nucleus, where RanGTP stimulates release of NLS cargo. In contrast, export receptors bind NES cargo in the nucleus together with RanGTP. Translocation of the receptor-NES cargo-RanGTP export complex to the cytoplasm is succeeded by GTP hydrolysis, which triggers disassembly of the complex and release of NES cargo and exportin (Ref.4).

The nucleotide state and subcellular distribution of Ran, both of which are critical for its ability to coordinate transport, are controlled by regulatory proteins. The generation of RanGTP occurs only in the nucleus by RanGEF that catalyzes GDP release and GTP binding. Conversion of RanGTP to RanGDP occurs in the cytoplasm and is mediated by an NPC-associated RanGAP1 and its co-activators, RanBP1 (Ran-Binding Protein-1) and RanBP2 (Ran-Binding Protein-2). The appropriate nucleocytoplasmic distribution of Ran is maintained by a balance between nuclear export of RanGTP, in association with transport receptors, and nuclear import of RanGDP mediated by NTF2 (Nuclear Transport Factor-2). The high concentration of RanGTP in the nucleus favor assembly of export complexes and disassembly of import complexes. The key regulatory proteins for Ran include RanGAP also called Rna1p, RanGAP co-activators (RanBP1 and RanBP2), the Ran import receptor NTF2, and RanGEF (also called RCC1). The cytoplasmic localization of RanGAP, RanBP1, and RanBP2 ensures that Ran in the cytoplasm is predominantly GDP-bound, whereas the nuclear localization of RanGEF ensures that Ran in the nucleus is predominantly GTP-bound. Identification of a release factor for RanGTP indicates, however, that the GTPase cycle involves an additional regulatory protein, Mog1 (Ref.5).

One potential function for Ran within the nucleus could be to regulate intra-nuclear transport events. In addition to movement between the nucleus and cytoplasm, there is also macromolecular trafficking that must occur within the nucleus. RNAs must move from their site of transcription to their site of action. For most newly synthesized cellular RNAs (e.g. messenger RNAs, transfer RNAs, ribosomal RNAs) this means that they must be appropriately targeted from nucleoplasmic genes to nuclear pore complexes for delivery to the cytoplasm. Many other classes of RNAs will ultimately function within the nucleus. Although some of these RNA species (e.g. spliceosomal small nuclear RNAs) are transported to the cytoplasm for processing and maturation, other RNAs (e.g. small nucleolar RNAs) exist solely within the nucleus and must be targeted from their site of transcription to their intra-nuclear site of action. Conceivably, RanGTP might be required for this intra-nuclear transport.